American Heart Association Scientific Sessions Embargoed Until Saturday Nov. 10, 2 pm CT, 3 pm ET The VITamin D and OmegA-3 TriaL (VITAL): Principal Results for Cardiovascular Disease and Cancer JoAnn E. Manson, MD, DrPH, FAHA Chief, Division of Preventive Medicine Brigham and Women's Hospital Professor of Medicine and the Michael and Lee Bell Professor of Women's Health Harvard Medical School Coauthors: J. Manson, N. Cook, I-M. Lee, W. Christen, S. Bassuk, S. Mora, H. Gibson, C. Albert, D. Gordon, T. Copeland, D. D’Agostino, G. Friedenberg, C. Ridge, V. Bubes, E. Giovannucci, W. Willett, J. Buring American Heart Association Scientific Sessions Chicago, Illinois November 10, 2018

Disclosures VITAL was supported by the U.S. National Institutes of Health: National Cancer Institute and National Heart, Lung and Blood Institute (co-sponsors) Additional NIH support: ODS, NINDS, and NCCIH (and ancillary study support from multiple institutes)  Pharmavite of Northridge, CA (vitamin D) and Pronova BioPharma of Norway and BASF (Omacor fish oil, known as Lovaza in the U.S. ) donated study pills, matching placebos, and calendar packaging.  Quest Diagnostics (San Juan Capistrano, CA) measured serum 25OHD and other biomarkers at no cost.  

The VITamin D and OmegA-3 TriaL (VITAL): Design Vitamin D3 (2000 IU/d); N=12,927 Placebo N=12,944 25,871 Initially Healthy Men and Women *Primary Prevention* (Men >50 yrs; Women >55 yrs) Placebo N=6464 EPA+DHA (1 gm/d [1.3:1 ratio]) N=6470 Placebo N=6474 EPA+DHA (1 gm/d [1.3:1 ratio]) N=6463 Median Treatment Period = 5.3 years. 5,106 African Americans. Blood collection in ~16,953 at baseline, follow-up bloods in ~6000. Adapted from: Manson JE, Bassuk SS, Lee I-M, et al. Cont Clinical Trials, 2011.

VITAL Specific Aims Primary Aims To test whether vitamin D3 and/or omega-3 fatty acids reduce risk of (a) major CVD events (composite of MI, stroke, CVD death), (b) total invasive cancer. Secondary Aims To test whether these agents lower risk of (a) MI/stroke/CVD death/PCI/CABG and (b) individual components of primary CVD outcome. To test whether these agents lower risk of (a) site-specific cancer, (b) total cancer mortality. Assess key subgroups, including age, sex, race/ethnicity, nutrient status at baseline.

Baseline Characteristics of the 25,871 VITAL Participants Mean age ± SD, years 67.1 ± 7.1 Sex, % female 13,085 (50.6) Race/ethnicity, % Non-Hispanic White 18,046 (71.3) African American 5,106 (20.2) Hispanic (not African American) 1,013 ( 4.0) Asian/Pacific Islander 388 ( 1.5) American Indian/Alaskan Native 228 ( 0.9) Mean body mass index (kg/m2) ± SD 28.1 (5.7) Current smoking, % 1,836 ( 7.2) Hypertension, treated, % 12,791 (49.8) High cholesterol, treated, % 9,524 (37.5) Diabetes, % 3,549 (13.7) Follow-up rates: morbidity (>93%); mortality (>98%). Study pill adherence: mean of >83% over 5.3-yr follow-up.

Hazard Ratios (HR) and 95% CIs of the CVD Outcomes by Randomized Assignment to Omega-3 Fatty Acids Omega-3s Placebo (N=12,933) (N=12,938) HR (95% CI) No. of Events Cardiovascular disease (1and 2 outcomes) Major CVD eventsa 386 419 0.92 (0.80-1.06) Major CVD + PCI/CABGb 527 567 0.93 (0.82-1.04) Total MI 145 200 0.72 (0.59-0.90)* Total stroke 148 142 1.04 (0.83-1.31) CVD mortality 142 148 0.96 (0.76-1.21) Other vascular outcomesc PCI 162 208 0.78 (0.63-0.95)* CABG 85 86 0.99 (0.73-1.33) Total CHDd 308 370 0.83 (0.71-0.97)* CHD death 37 49 0.76 (0.49-1.16) Fatal MI 13 26 0.50 (0.26-0.97)* aPrimary outcome. A composite of MI, stroke and CVD mortality. bExpanded CVD composite cNot prespecified as primary or secondary outcomes. dA composite of MI, PCI/CABG, and CHD death. All analyses are intention-to-treat. *Nominal p-value <0.05. For MI, the nominal p-value was 0.003.

Cumulative Incidence Rates of Major CVD Events and Total MI by Year of Follow-up: Omega-3s vs. Placebo Major CVD Events Total MI For Major CVD Events: p-value = 0.24 For Total MI: nominal p-value = 0.003 and Bonferroni-adjusted p-value = 0.015.

Excluding the first 2 years of follow up: Hazard Ratios (HR) and 95% CIs of Major CVD Events and Total MI after Excluding Early Follow-up (Omega-3s vs. Placebo) Excluding the first 2 years of follow up: Omega-3s Placebo (N=12,933) (N=12,938) HR (95% CI) No. of Events Major CVD events 269 301 0.89 (0.76-1.05) Total MI 94 131 0.72 (0.55-0.93)* *Nominal p-value <0.05.

Hazard Ratios of Major CVD Events by Baseline Fish Consumption, Comparing Omega-3 Fatty Acids and Placebo Groups Subgroups Total Omega-3s Placebo HR (95% CI) Interaction No. of Events p-value Fish Consumption 0.045 (servings/wk) 25,435 <median 13,514 189 232 0.81 (1.5 servings/wk) (0.67-0.98) >median 11,921 189 176 1.08 (1.5 servings/wk) (0.88-1.32) n-3 fatty acids better placebo better Hazard Ratios 1.6 0.6 0.8 1.4 1.2 1

Hazard Ratios of Total MI by Subgroups, Comparing Omega-3 Fatty Acids and Placebo Groups Interaction Subgroups Total Omega-3s Placebo HR (95% CI) p-value No. of Events Race 25,304 0.001 Non-Hispanic White 18,046 126 135 0.93 (0.73-1.18) African American 5,106 9 39 0.23 (0.11-0.47) Other 2,152 8 16 0.54 (0.23-1.26) Fish Consumption (servings/wk) 25,435 0.048 <median 13,514 74 121 0.60 (0.45-0.81) (1.5 servings/wk) >median 11,921 67 72 0.94 (0.67-1.31) (1.5 servings/wk) # of Cardiovascular Risk Factors 25,871 0.047 No risk factors 7,802 41 40 1.01 (0.65-1.56) 1 risk factor 8,948 53 70 0.75 (0.53-1.08) 2 or more risk factors 9,121 51 90 0.57 (0.41-0.81) 0.1 0.2 0.4 0.6 1 1.6 Hazard Ratios n-3 fatty acids better placebo better

Hazard Ratios (HR) and 95% CIs of the Cancer Outcomes and All-Cause Mortality (Omega-3s vs. Placebo) Omega-3s Placebo Outcome (N=12,933) (N=12,938) HR (95% CI) No. of Events Total invasive cancer 820 797 1.03 (0.93-1.13) Cancer death 168 173 0.97 (0.79-1.20) All-cause mortality 493 485 1.02 (0.90-1.15) Excluding the first 2 years of follow up: Total invasive cancer 536 476 1.13 (1.00-1.28) Cancer death 126 135 0.93 (0.73-1.19) All-cause mortality 371 381 0.97 (0.84-1.12)

Hazard Ratios (HR) and 95% CIs of the CVD Outcomes by Randomized Vitamin D Assignment Vitamin D Placebo (N=12,927) (N=12,944) HR (95% CI) No. of Events Cardiovascular disease (CVD) (1and 2 outcomes) Major CVD eventsa 396 409 0.97 (0.85-1.12) Major CVD + PCI/CABGb 536 558 0.96 (0.86-1.08) Total MI 169 176 0.96 (0.78-1.19) Stroke 141 149 0.95 (0.76-1.20) CVD mortality 152 138 1.11 (0.88-1.40) Other vascular outcomesc PCI 182 188 0.97 (0.79-1.19) CABG 73 98 0.75 (0.55-1.01) MI death 24 15 1.60 (0.84-3.06) Stroke death 19 23 0.84 (0.46-1.54) aPrimary outcome. A composite of MI, stroke and CVD mortality. bExpanded CVD composite. cNot prespecified as primary or secondary outcomes.

Hazard Ratios (HR) and 95% CIs of Major CVD Events Comparing Vitamin D and Placebo Groups, According to Baseline Characteristics (Prespecified Subgroups) Major Cardiovascular Events No. of Events Interaction Total Vitamin D Placebo (95% CI) P-value Baseline Serum 25(OH)Da 15,787 0.75 <20 ng/mL (50 nmol/L) 2,001 34 34 1.09 (0.68-1.76) ≥20 ng/mL (50 nmol/L) 13,786 218 216 1.00 (0.83-1.21) Baseline Serum 25(OH)Da 15,787 0.42 <cohort median 7,812 128 139 0.94 (0.74-1.20) ≥cohort median 7,975 124 111 1.09 (0.84-1.41) Omega-3 Fatty Acids Randomization Status 25,871 0.56 Placebo group 12,938 210 209 1.01 (0.83-1.22) Omega-3 group 12,933 186 200 0.93 (0.76-1.14) a25OHD = 25 hydroxyvitamin D.

Hazard Ratios (HR) and 95% CIs of the Cancer and All-Cause Mortality by Randomized Vitamin D Assignment Vitamin D Placebo (N=12,927) (N=12,944) HR (95% CI) No. of Events Total invasive cancer 793 824 0.96 (0.88-1.06) Cancer death 154 187 0.83 (0.67-1.02) All-cause mortality 485 493 0.99 (0.87-1.12) Excluding the first 2 years of follow up Total invasive cancer 490 522 0.94 (0.83-1.06) Cancer death 112 149 0.75 (0.59-0.96)* All-cause mortality 368 384 0.96 (0.84-1.11) *Nominal p-value = 0.024.

Side Effects/Adverse Events No significant side effects with either agent. No increased risk of hypercalcemia with vitamin D. No increased risk of bleeding with omega-3s. GI symptoms were not increased by either agent. Ancillary Studies in VITAL (partial list) Diabetes/Glucose Tolerance Cognitive Function Hypertension Heart Failure Atrial Fibrillation Autoimmune Disorders Fractures/Bone Health Asthma/Respiratory Diseases Kidney Disease Mood Disorders/Depression Infections Several others

Conclusions Neither omega-3s nor vitamin D significantly reduced the primary endpoints of major CVD events or total invasive cancer. Omega-3s reduced total MI by 28% (nominal p-value=0.003, Bonferroni-adjusted p-value=0.015), with greatest reductions in those with low dietary fish intake and in African Americans. PCI, fatal MI, total CHD (MI + coronary revasc + CHD death) were also reduced. Vitamin D reduced total cancer mortality in analyses excluding early follow up.

Thank You! Thank you to VITAL Participants, Investigators, and Staff! VITAL Coauthors D. Gordon H. Gibson D. D’Agostino C. Albert T. Copeland J. Buring V. Bubes E. Giovannucci G. Friedenberg W. Willett C. Ridge I-M. Lee N. Cook W. Christen S. Mora J. Manson S. Bassuk VITAL DSMB Members: N. Wenger (chair), L. Cohen, T. Colton, M. Espeland, C. Henderson, A. Lichtenstein, R. Silliman Thank You!